The main industrial method for preparation of pure enantiomers constitutes the resolution of racemates. The present invention relates to the production of pure enantiomer of arylpropionic acid selected from profen family of drugs such as ibuprofen, flurbiprofen, flunoxaprofen, naproxen etc. The methods for such resolution include: direct preferential crystallization, crystallization of the distereomeric salts, kinetic resolution, enzymatic resolution, differential absorption and asymmetric synthesis.
The Industrial processes for production of drugs such as Amoxycillin, Ampicillin, Captropril, Diltiazem, Naproxen, Cefalexin, Cefadroxil, Timolol, .alpha.-methyl L-dopa, chloramphenicol, Dextromethorphan and Ethambutol etc. use racemate resolution via crystallization. Technical feasibility of such processes is restricted to conglomerates which are less than 20% of all racemates. In case of true racemic compounds, the seeding of one enantiomer does not separate the other enantiomer by preferential crystallization.
The conglomerate exhibits a minimum melting point for the racemic mixture while a racemic compound shows a maximum melting point. The success of preferential crystallization depends on the fact that the two enantiomers crystallize at different rates and on the correlation between the melting point diagram and the solubility phase diagram, i.e., the mixture having the lowest melting point is the most soluble, and for a conglomerate this is the racemic mixture. Ibuprofen is a true racemic compound.
If the true racemic compound is a homogeneous solid phase of two enantiomers co-existing in the same unit cell, it may be separated by diastereomer crystallization, this generally involves a reaction of the racemate with an optically pure acid or base (the resolving agent) to form a mixture of diastereomeric salts which is separated by crystallization.
Diastereomeric crystallization is widely used on Industrial scale. A typical example is production of D(-)Phenyl glycine, an antibiotic intermediate, using camphor sulphonic acid as a resolving agent. There are natural and semi-synthetic resolving agents such as Tartaric acid, Maleic acid, Camphor sulphonic acid, Mandelic acid, Phenoxy propionic acid, hydratopic acid, Brucine, Quinine, Ephedrine, .alpha.-Methylbenzylamine, Amphetamine, Deoxyehedrine, and N-Methyl D-Glucamine etc.
The theoretical once-through yield of a resolution via diastereomer crystallization is 50 percent. However, in practice, a single re-crystallization produces a composition that is simply an enantiomerically enriched racemate. This means that the innovation, if any, may come at this particular stage of unit process/operation.
Another method for the resolution of racemates is the kinetic resolution, the success of which depends on the fact that the two enantiomers react at different rates with a chiral addend. The industrial process such as production of S-Naproxen by CCL-catalyzed and enzymatic hydrolysis of the methyl ester, was reported by Sih and Coworkers (Sih, C. J., Gu, Q. M. Fulling, G., Wu, S. H. and Reddy, D. R., Dev. Ind. Microbiol., 29, 221-229(1988), Gu, Q. M., Chen, C. S., and Shih, C. J., Tetrahedron Lett, 27, 1763(1986)).
The enantioselective conversion of a prochiral substrate to an optically active product, by reaction with a chiral addend, is referred to as an asymmetric synthesis. The manufacture of L-Dopa by Monsanto is a typical industrial example. See Knowles, et. Al., J. Am. Chem. Soc., 97, 2567(1975).
With the exception of the preferential crystallization process, when applied to Ibuprofen, the prior art processes typically produce a first mixture that is essentially an enantiomerically enriched racemic composition. A number of crystallizations are required to yield the pure enantiomer.
Numerous processes for the preparation of S(+)-Ibuprofen have been disclosed, most relate to resolution.
The use of S(-)-.alpha.-methylbenzylamine as the resolving agent has been described in the patent and non-patent literature. Kaiser et. al., J. Pharm. Sci., 65(2), 269-274 (1976), discloses the separation of (S)-Ibuprofen from racemic Ibuprofen. U.S. Pat. No. 4,209,638 (Nicholson et. al.) discloses a process for increasing the proportion of desired enantiomer from racemic phenyl propionic acid (such as Ibuprofen) by a partial dissolution technique. U.S. Pat. No. 4,983,765, (Lukas et. Al.) discloses a separation process in which the reaction to a diasteriomeric salt takes place in a polar solvent, and the salt is purified by several crystallizations to produce optically pure material U.S. Pat. No. 5,015,764 (Manimaran et. al.) discloses a process in which the racemic mixture is initially treated with an organic or inorganic base to form a salt solution, and the salt solution is treated with a chiral base such as (S)- .alpha.-methylbenzylamine to precipitate the less soluble diastereomeric salt from the reaction solution, and PCT Published Application No. WO 93/15040 (Ethyl Corporation) discloses an invention wherein an inorganic or organic salt soluble in the solution of the resolution process, is added to enhance the separation. The process discloses the use of an inert organic or an inorganic salt such as triethylamine, preferably an alkali metal, alkaline earth metal or ammonium salt, most preferably sodium, potassium or ammonium salts of halides (fluoro, chloro, bromo or iodo salts) to enhance separation of less soluble diastereomer from mixture. Nitrates and acetate salts are also useful in the process of the above application Especially preferred is sodium chloride. It can be added at different stages of the process to improve separation of less soluble diastereomer.
U.S. Pat. No. 4,994,604 (Tung et. al.) discloses the use of (S)-lysine in a preferential crystallization method for the formation of the (S)-Ibuprofen(S)-lysine salt; and U.S. Pat. No. 5,332,834 (Bhattacharya et. al.) discloses an improvement on that process including the racemization and recycle of (R)-Ibuprofen. European Patent No. 0529835 (Nagase & Co.) discloses the use of various optically active phenyl substituted amines, such as 2-(4-methylphenyl)-3-methylbutylamine, as resolving agents.
U.S. Pat. No. 4,246,164 (Felder et. al.) discloses the use of N-methyl-D-glucamine and U.S. Pat. Nos. 4,246,193 and 4,515,811 (Holten) disclose the use of other N-alkyl-D-glucamines as resolving agents in the preparation of Naproxen.
U.S. Pat. No. 4,501,727 (Armitage et. al.) discloses N-methyl-D-glucamine salt of (+)-flurbiprofen although it does not disclose it as a resolving agent.
U.S. Pat. No. 5,621,140 (George et. al.) discloses a Ibuprofen resolution process using N-methyl-D-glucamine [6284-40-8] and N-octyl-D-glucamine. The S-Ibuprofen yield is 73.2% and 74% and ee is 99% and 99.9% respectively.
U.S. Pat. No. 5,599,969 (Robert Hardy et. al.) discloses a process of Ibuprofen resolution using (S)-.alpha.-methylbenzylamine. The process produces S-Ibuprofen of 89.3% purity (by weight). It discloses resolution methods for phenyl propionic acid in general covering Ibuprofen, flurbiprofen and their pharmaceutically acceptable salts.
U.S. Pat. No. 5,189,208 (G. Patrick Stably and Baton Rouge, La.) discloses an Ibuprofen resolution process using a non racemic Ibuprofen as its starting material obtained from an enantioselective synthesis process.
The enantiomeric excess is enriched by removing close to racemic composition as crystals leaving behind an enriched S-enantiomer of Ibuprofen in mother liquor.
In another pending Indian Patent Application No. 286DEL/95 filed in 1995 by N. K. Yadav and B. D. Kulkarni filed for Enantioselective separation of chiral drugs, the application of surfactant and co-surfactant along with some deemulsifying agent, such as NaCl, produces optical/activity of organic aqueous phases indicating that the system can be used for enantioselective separation of chiral drugs into enantiomers.